Clinical benefit early in urate-lowering treatment of gout is difficult to document. We examined data from 1,832 gouty subjects treated with either urate-lowering agents or placebo to identify determinants of gout flare incidence and tophus size during year 1 of treatment. Reductions from pretreatment serum urate levels influenced flare frequency and tophus size, but the effect of urate level on flare incidence was biphasic. Lower urate levels were associated with higher flare incidence early in treatment but lower incidence by one year. The complex relationship between urate-lowering and clinical outcome early in treatment has implications for both clinical and investigative approaches to urate-lowering management.